ArticleAmerican journal of human genetics2021
High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29citing papers in PubMed
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29 citing papers in PubMed, 57 citations in OpenAlex.
- Using a modular massively parallel reporter assay to discover context-dependent regulatory activity in type 2 diabetes-linked noncoding regions.HGG advances · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Synonymous and non-synonymous variants at splice junctions can disrupt splicing and are frequently linked to disease associated loss of function genes.BMC genomics · 2025Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- Massively parallel assay of human splice variants reveals cis-regulatory drivers of disease-associated and cell type-specific splicing regulation.bioRxiv : the preprint server for biology · 2025Article
- Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4.Nature structural & molecular biology · 2025Article
- A high-fat diet suppresses growth hormone synthesis and secretion by influencing the Vit D receptor and Pit1.Endocrine · 2025Article
- Hypopituitarism: genetic, developmental, and acquired etiologies with a focus on the emerging concept of autoimmune hypophysitis.Endocrine journal · 2025Review
- From computational models of the splicing code to regulatory mechanisms and therapeutic implications.Nature reviews. Genetics · 2025Review
- Common and Uncommon Mouse Models of Growth Hormone Deficiency.Endocrine reviews · 2024Review
- Decoding biology with massively parallel reporter assays and machine learning.Genes & development · 2024Review
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation.American journal of human genetics · 2024Article
- Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.Reviews in endocrine & metabolic disorders · 2024Review
- Knockout mice with pituitary malformations help identify human cases of hypopituitarism.Genome medicine · 2024Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.Genome biology · 2023Article
- High-Throughput Splicing Assays Identify Known and NovelKidney international reports · 2023Article
- Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup.American journal of human genetics · 2023Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.bioRxiv : the preprint server for biology · 2023Article
- APPLICATION OF THE ACMG/AMP FRAMEWORK TO CAPTURE EVIDENCE RELEVANT TO PREDICTED AND OBSERVED IMPACT ON SPLICING: RECOMMENDATIONS FROM THE CLINGEN SVI SPLICING SUBGROUP.medRxiv : the preprint server for health sciences · 2023Article
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Authors and funding
34 authors at 12 institutions in 6 countries.
Peter GergicsDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Cathy SmithDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218, USA.
Hironori BandoDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Alexander A L JorgeGenetic Endocrinology Unit (LIM25), Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brazil.
Denise Rockstroh-LippoldDepartment of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany.
Sebastian A VishnopolskaInstituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Frederic CastinettiAix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France.
Mariam MaksutovaDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Luciani Renata Silveira CarvalhoDevelopmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
Julia HoppmannDepartment of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany.
Julián Martínez MayerInstituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Frédérique AlbarelAix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France.
Debora BraslavskyCentro de Investigaciones Endocrinológicas "Dr. César Bergadá," FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Ana KeselmanCentro de Investigaciones Endocrinológicas "Dr. César Bergadá," FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Ignacio BergadáCentro de Investigaciones Endocrinológicas "Dr. César Bergadá," FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Marcelo A MartíDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales CONICET, Pabellòn 2 de Ciudad Universitaria, Ciudad de Buenos Aires, CABA C1428EHA, Argentina.
Alexandru SaveanuAix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Laboratory of Molecular Biology, Marseille 13385, France.
Anne BarlierAix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Laboratory of Molecular Biology, Marseille 13385, France.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany.
Michael H GuoDivision of Endocrinology, Boston Children's Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Andrew DauberCincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Marilena NakagumaDevelopmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
Berenice B MendoncaDevelopmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
Sajini N JayakodyDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
A Bilge OzelDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Qing FangDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Qianyi MaDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Jun Z LiDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Thierry BrueAix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France.
María Ines Pérez MillánInstituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.
Ivo J P ArnholdDevelopmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
Roland PfaeffleDepartment of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany.
Jacob O KitzmanDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218, USA. Electronic address: kitzmanj@umich.edu.
Sally A CamperDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA. Electronic address: scamper@med.umich.edu.
University of Michigan–Ann Arbor · USUniversidade Cidade de São Paulo · BRUniversity of Buenos Aires · ARGénétique Médicale & Génomique Fonctionelle · FRUniversity Hospital Leipzig · DECentre de Génétique Médicale de MarseilleHôpital de la Conception · FRHospital Nacional de Niños · CRLeipzig University · DEUniversidade de São Paulo · BRUniversity of Lübeck · DEWest Chester University · US
Funding
Hypopituitarism: role of PROP1 and retinoic acid signaling in regulation of pituitary stem cell differentiationR01HD097096 · NICHD · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CAMPER, SALLY A. · 2019 to 2023
$2.2MMassively parallel experimental measurement of variant functional impactsR01GM129123 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KITZMAN, JACOB OTTO · 2018 to 2022
$2.1MHigh Throughput Functional Assessment SHH Signaling Variants Identified in Patients with Craniofacial Defects and HypopituitarismR03DE031037 · NIDCR · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CAMPER, SALLY A., KITZMAN, JACOB OTTO · 2021 to 2022
$230kNICHD NIH HHS R01 HD097096NIDCR NIH HHS R03 DE031037NIGMS NIH HHS R01 GM129123
Abstract
Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
Indexed as
MutationAdolescentAdultChildChild, PreschoolHigh-Throughput Screening AssaysHumansHypopituitarismMalePedigreePituitary HormonesRNA SplicingTranscription Factor Pit-1Pituitary HormonesPOU1F1 protein, humanTranscription Factor Pit-1alternative splicinggrowth hormone deficiencyhypopituitarismmassively parallel splicing assaymultiplexed assays of variant effectsPIT-1transcriptional regulationvariants of uncertain significance
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